ES2230564T3 - FERRIC COMPOUNDS, COMPOSITIONS, METHODS OF MANUFACTURE OF THESE AND ITS USED. - Google Patents

Abstract

The present invention is directed to complexes comprising iron in the ferric state and a hydroxypyrone. The present invention is also directed to methods of making such complexes and to the use of such complexes in the treatment and prevention of iron deficiency disorders including iron deficiency anaemia.

Description

Ferric compounds, compositions, methods of manufacture of these and their uses.

The present invention relates to compounds iron for use in medicine, especially in the treatment and iron deficiency anemia prevention and manufacturing methods these compounds.

In men and animals an essential requirement is a adequate supply of iron for tissue growth. Although there is usually a large amount of iron in the diet, the iron absorption level of food is generally low so that the supply of iron to the body can become Easily critical in a variety of conditions. Anemia Iron deficiency is commonly found in pregnancy and can also represent a problem for the newborn. Also in certain pathological states where there is loss of blood, or where there is a bad distribution of iron in the body, there may be a state of chronic anemia. This is seen in diseases such as Crohn's disease, rheumatoid arthritis, certain diseases hemolytic and cancer.

Ferrous iron (Fe II) is a strong reducing agent and can also interact and damage proteins, carbohydrates and lipids and therefore is harmful for the body. Therefore it is better to release it to the body and keep it in the body in the ferric state (Fe III). However it is difficult do so because its solubility and therefore its bioabsorption is poor. The absorption rate of ferric salts such as ferric sulfate it is typically 30% when given to an empty stomach but this produces unpleasant side effects, particularly with chronic medication When it occurs with food, absorption can fall to 1 to 3% of the administered dose. For some Anemia requires a daily uptake of 30 milligrams of iron and although a wide range of iron compounds is already marketed for the treatment of iron deficiency anemia, the poor levels of iron uptake by the body from these Compounds need relatively high levels of dose. Without However, the administration of high doses of iron complexes poorly absorbed can cause siderosis of the intestinal wall and a variety of side effects like stomach ache, nausea, vomiting, constipation and heavily dark stools that may result in poor compliance with treatment by the patient.

GB 2128998 and EP 0159194 describe complexes of iron ferric iron several 3-hydroxy-4-pyrones in a molar ratio iron: hydroxypyrone of 1: 3. Complexes of describe for use at relatively low dose levels for ferric compounds in the treatment of anemia due to deficiency of iron. These complexes were intended to be transferred in the gastrointestinal cell in the body and then dissociated to provide iron for absorption and transfer in the process Natural body uptake. However, the complexes of iron described in the previous documents suffer from significant problem that consists in whether the dissociation of complexes occur in an unfavorable environment in the body, especially in the gastrointestinal tract, iron can form native that precipitates and therefore is not absorbed.

GB 2128998 teaches that only a neutral complex comprising maltol and iron in the iron state in a molar ratio of 3: 1 (maltol: iron) confers a therapeutic effect. In contrast, complexes loaded with maltol: 1: 1 or 2: 1 molar ratios show by in vitro tests that they are unsatisfactory so that the iron of these complexes is not expected to be absorbed to a satisfactory degree in vivo , making them inadequate For use in medicine.

It is an object of the present invention to provide iron complexes for use in medicine, notably in the iron deficiency anemia treatment, which complexes do not suffer from, or substantially mitigate the above and other problems of known complexes.

It is also an object of the invention to provide methods for manufacturing iron complexes and compositions Pharmaceuticals

According to a first aspect, the invention provides an iron complex comprising iron in the ferric state and hydroxypyrone binder; characterized in that iron and Hydroxypyrone binder are provided in combination with an acid carboxylic, more preferably a hydroxycarboxylic acid as counterion

Preferably, the carboxylic acid is an acid C 1 to C 6, particularly those with 1 to 3 groups carboxylic.

Preferably, the acid is selected from one or more of citric acid, isocitric acid, gluconic acid, succinic acid, fumaric acid and tartaric acid. Conveniently it is tribasic acid, citric acid, and is present in a formulation in an amount sufficient to generate a concentration in blood solution from 0.1 to 100 mM at continued administration, preferably in an amount 10 to 1000 mg per dose.

It will be appreciated that carboxylic acids such as Citric acid, being ionic chelators, would be expected to form binder complexes mixed with the iron chelates of the hydroxypyrones mentioned above, but these complexes would have saturated. Surprisingly, when citric acid was added to iron complexes of 3-hydroxy-4-pyrones no binder complexes were identified, but in solution the Citric acid behaves like a counterion (anion) with the complex iron / hydroxypyrone, helping to keep more iron in solution and available for absorption.

Unlike the neutral chelated mixed binder complexes mentioned in GB 2 157 686 A
(National Research Development Corporation), in which there is an internal balance of charges between the ferric cation and covalently bound binders (see page 1, lines 45 to 48), it is understood that carboxylic acid acts as a counterion ( non-covalently bound anion) in the complexes of the invention.

Certain aspects of carboxylic acid that contains compositions of the first aspect of the invention can improve the activity of iron complexes in contexts private individuals Thus, although neutral iron complexes containing a 1: 3 molar ratio of iron: hydroxypyrone are special value for being stable over a wide range of pH values from about 4 to 5 to 10, if administered orally, dissociate at pH values less than 4 that predominate in the stomach to form a mixture of 1: 2 and 1: 1 complex together with binder free. Unexpectedly, the presence of carboxylic acid improves the solubility of these intermediate complexes instead of the formation of mixed binder complexes and any excess iron generated is trapped as carboxylated iron instead of precipitating as insoluble hydrated iron that is not usable for bioabsorption This effect is entirely unexpected because an acid carboxylic as citrate by itself is very poor in improving iron transport through cell membranes. Conveniently, the presence of a carboxylic acid as a Citrate also maintains solubility in the wide pH range It is found in the upper intestinal tract.

The pH of the stomach can vary before and after of meals and may also be dependent on other medications as antacids The improved solubility provided by the compositions of the invention provide a more iron supply regular and reproducible on a daily basis than the compositions known.

In a further aspect, the invention provides a method for preparing iron complexes according to a first aspect of the invention comprising reacting ferric ion with at least one hydroxypyrone and combine the resulting complex with carboxylic acid, preferably citric acid.

The hydroxypyrone iron complexes of the invention can be prepared by dissolving iron carboxylate (III), especially citrate, in non-buffer water at concentration from 0.1 to 1 M. An amount of hydroxypyrone dissolved in a solvent in the 1: 1: 1 molar ratio iron / hydroxypyrone / carboxylic acid with rapid agitation. This guarantees that the reaction is non-covalent, that is, the acid carboxylic acts as counterion. In the preferred method using 1: 1 molar ratios of iron citrate to dissolved ethylmaltol in ethanol, a deep red colored solution of citrate 2- [Fe III] ethylmaltol] 2+. After Stirring for 15 minutes, the ethanol is removed by evaporation at atmospheric pressure. The resulting solution is freeze dried to produce an intense red powder.

Alternatively, iron complexes are prepared according to the methods described in example 1 of GB 2128998 and EP 0159914, by the reaction of a mixture of compounds that provides the binders and iron ions, the last being conveniently derived from an iron salt, particularly a ferric halide and especially ferric chloride. Then you add a carboxylic acid as citrate to the resulting iron complexes to form complexes of the first aspect of the invention with the carboxylic acid as counterion. It will be understood that the amounts Relative components are selected to produce a relationship 1: 1: 1 molar of iron complex: hydroxypyrone: acid carboxylic.

To obtain a preferred liquid preparation of the complexes of the first aspect of the invention are reacted a solution of iron (Fe III) with hydroxypyrone and an acid carboxylic, preferably tribasic acid citrate, is added until a 1: 3 molar ratio precipitate forms iron / hydroxypyrone The precipitate is extracted and the supernatant comprises a liquid preparation of a mixture of 1: 1 and 1: 2 of complexes of Iron hydroxypyrone with citrate as an anion.

Preferably, the iron concentration is from 0.01 M to 1 M and the solution stabilizes at a pH from 3.0 to 7.0. Preferably, the hydroxypyrone is maltol or ethylmaltol.

It will be understood that iron / hydroxypyrone complexes with a carboxylic acid as citrate according to a first aspect of the invention can also be formed in vivo by administering the iron / hydroxypyrone complex and carboxylic acid sequentially instead of simultaneously. In vivo , the acid can act as a counterion to improve the solubility of iron. This manufacturing method is proposed to fall within the scope of the first aspect of the invention.

The invention also relates to the use of a iron complex as defined above for the first aspect of the invention, in the manufacture of a composition for use in medicine.

The invention also relates to the use of a iron complex according to the first aspect of the invention in the manufacture of a composition for use in animals as well as For human use. Preferably, the medical use is in the treatment or prevention of iron deficiency anemia.

Preferably, hydroxypyrone is a hydroxy-4-pyrone, and especially a 3-hydroxy-4-pyrone or a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to atoms of ring carbon are replaced by an aliphatic hydrocarbon group from 1 to 6 carbon atoms, or a 5-hydroxypyrone, as Kojic acid.

The substituted 3-hydroxy-4-pyrones may carry more than one type of aliphatic hydrocarbon group but it is not usual and substitution by one is preferred instead of two or three aliphatic hydrocarbon groups. The term "aliphatic hydrocarbon group" is used herein to include acyclic and cyclic groups that can be unsaturated or saturated, the acyclic groups having branched chains or especially a straight chain. Those of greatest interest are groups of 1 to 4 carbon atoms and especially 1 to 3 carbon atoms. Saturated aliphatic hydrocarbon groups are preferred, these cyclic groups being cycloalkyl, cyclopropyl and especially cyclohexyl groups or more particularly, acryl groups such as n-propyl and isopropyl alkyl groups and especially ethyl and methyl. The substitution in position 2- or 6- is of special interest, although when the ring is replaced by the larger aliphatic groups, it may be an advantage to avoid substitution on an alpha carbon atom to the system
one

This system is involved in the formation of iron complexes and the close proximity of one of the groups aliphatic hydrocarbon can lead to steric effects that inhibit complex formation.

By the following formulas (I), (II) and (III) Examples of specific compounds whose complexes are shown Iron are for use in the present invention:

2

in which R is a group cycloalkyl or alkyl, for example, methyl, ethyl, n-propyl or isopropyl. Among these compounds the 3-hydroxy-2-methyl-4-pyrone (maltol; II, R = CH 3) is the one of greatest interest, although the 3-hydroxy-pyrone (acid pyromeconic; I), the 3-hydroxy-6-methyl-4-pyrone (III, R = CH 3) and particularly the 2-ethyl-3-hydroxy-4-pyrone (ethylpyromeconic acid; II, R = C2H5) are also of special interest For convenience the compound 3-hydroxy-2-methyl-4-pyrone  is called here "maltol".

Certain hydroxypyrones such as maltol are commercially available. With others, a starting material convenient in many cases is 3-hydroxy-4-pyrone which is easily obtained by decarboxylation of 2,6-dicarboxy-3-hydroxy-4-pyrone (meconic acid). For example, the 3-hydroxy-4-pyrone can be reacted with aldehyde to insert a group hydroxyalkyl in position 2, which group can then be reduced to produce 2-alkyl-3-hydroxy-4-pyrone. The preparation of 2-ethyl-3-hydroxy-4-pyrone, etc., this way is described in the published application US number Series 310,141 (1960 series). Other preparation methods have been described by Spielman, Freifelder, J. Am. Chem. Soc. Vol. 69 Page 2908 (1947).

It will be understood by experts who These are not the only routes available for these compounds and their iron complexes and several alternatives can be used.

Conveniently, iron ion is provided in combination with 3-hydroxy-4-hydroxypyrone as a molar ratio complex iron: hydroxypyrone 1: 3, 1: 2 or 1: 1.

In a second aspect, the invention provides a method of producing a composition comprising mixing a ferric iron compound, other than an inorganic ferric salt, and a hydroxypyrone, where the iron compound and hydroxypyrone they are combined in a dry state and the mixture also comprises an acid carboxylic. The compositions obtained are for use in medicine.

By "dry state" we include the sense that the components are supplied in a way substantially free of water. Preferably, the components are in powder form

Through "inorganic salt" we include ferric nitrate, ferric sulfate and ferric halides such as ferric chloride. Preferably, the ferric iron compound comprises a carboxylic acid such as citrate, advantageously ammonium citrate, or tartrate. The carboxylic acid can also be added separately to the mixture as it is or preferably as a complex with iron. The carboxylic acid appears to promote the formation of ferric monohydroxypyronas species, that is a 1: 1 molar ratio complex (iron: hydroxypyrone) in aqueous solution or in vivo .

The carboxylic acid component of the mixture It may be present in excess. Preferably, the method includes furthermore the addition of a pharmaceutically diluent or carrier acceptable to the mixture simultaneously or subsequently.

Using a "dry combination" method of the invention one can easily vary the relative proportions of the components to produce any iron molar ratio to hydroxypyrone that is required. In particular the method provides a simple way to produce compositions in which the relationship Molar iron to hydroxypyrone is less than 1: 3, especially 1: 2 and 1: 1.

In a preferred embodiment the components of the mixture is ferric carboxylate and ferric hydroxypyrone complex in a molar ratio iron: hydroxypyrone 1: 3. Preferably, the components are supplied in relative quantities whereby the molar ratio iron: hydroxypyrone: carboxylic acid in the resulting mixture is 1: 1: 1.

The inventors have shown that in solution aqueous this mixture produces ferric monohydroxypyrone species that shows greater solubility than the individual components of the mixture. For example, ferric citrate and ferric trimaltol they have a respective solubility of less than 10 mg / ml at pH 7.0. Without However, when used in the dry combination method of the preferred embodiment, the 1: 1: 1 molar ratio mixture (iron: maltol: citrate) exhibits a solubility of more than 100 mg / ml, it is that is, more than ten times greater than that of ferric citrate and ferric trimaltol. This synergistic effect is completely unexpected.

It seems that, in aqueous solution, the mixture is reorganizes to form highly soluble iron chelates that comprise iron molar ratio complex: maltol 1: 1 with up to approximately 25% of iron complexes: maltol 1: 2, of the ratio of ferric citrate to ferric trimaltol in the method Dry combination The carboxylic acid (for example, citrate) it seems to act as a counterion throughout the pH range, although There may be some partial chelation. Also, the inventors have discovered that the compositions produced by the above method Dry combination are stable in a wide pH range.

The present inventors have discovered that, contrary to their expectations in view of GB 2128998, iron: hydroxypyrone complexes with molar ratios of 1: 1 or 1: 2 (iron: hydroxypyrone), especially 1: 1, are well assimilated in vivo , making them suitable for increasing the level of iron in the patient's blood flow.

The complexes according to the invention are surprisingly stable for extended periods (for example, six months) in a wide pH range. This is advantageous, because the amount of hydroxypyrone, and therefore the cost of production, is reduces compared to neutral compositions iron: maltol 1: 3. In addition, a reduced amount of hydroxypyrone allows them to be made preparations containing less than the acceptable daily intake (ADI) recommended by the World Health Organization (WHO) for these hydroxypyrones. This makes the preparations of the invention suitable for nutritional / free acquisition (OTC) use.

The complex solutions of the invention, have unexpected stability even at high concentrations and at acidic to neutral pH values. For example, although the pH Natural ferric monomaltol is approximately 2.8, presents stability for extended periods (for example, six months) in a stabilized pH of 7. This is unexpected because all the others soluble forms of ferrous ion such as SO4 Fe precipitate very quickly at pH 7.

Therefore, the complexes of the invention can be used in the production of liquid formulations for use in medicine. As the liquid formulation can be stabilized at a pH value physiologically acceptable, this is at a pH value such as neutral pH 7 where it is absent or at a level satisfactory administration irritation, formulations Liquids are suitable for intravenous or intramuscular injection. They are also less irritating than acid solutions when administered orally because acidic solutions can produce irritation, especially in the duodenum.

It will be understood that several can be used buffering agents to stabilize the pH of liquid formulations of the invention around the neutral to make them especially suitable for administration by injection. The examples of Suitable buffer agents include bicarbonates, sodium acetate, amino acids such as lysine and various weak carboxylic acids not chelators

It will be understood that neutral complexes 1: 3 molar ratio of ferric iron: 3-hydroxy-4-pyrone they are unsuitable for formulation as liquids due to their poor solubility (approximately 4 mg / ml). You would need to drink a unacceptably large volume of such liquid formulations for get enough iron absorption.

Iron sorbitol (eg Jectofer? - 2 ml ampoules of 50 mg / ml ferrous ion, sold by Astra UK) is known for intramuscular injection in the treatment of anemia due to iron deficiency when oral administration is not effective, but not suitable for intravenous injection.

Initial toxicity studies of the inventors have shown that the liquid formulations of the complexes of the invention do not produce red blood cell hemolysis or breakage of red blood cells, making them suitable for injections. This occurs in contrast to the published results of Rice-Evans and Baysal (J. Biochem. 1987 244 , 191-196), which demonstrated that iron salts damage red blood cells and are too toxic for injection.

The inventors have also shown that Liquid formulations of complexes of the invention induce when they incubate with hemoglobin (Hb) relatively little formation of methemoglobin (met-Hb) (less than 5% in 2½ hours). It would be undesirable to form met-Hb in the blood, a stable Hb oxidation product, with a formulation injectable Met-Hb formation has been suggested as an indicator of free radical damage and therefore of toxicity.

The effectiveness of iron absorption using complex solutions of the invention is very surprising in view of the conclusions of Seeberg et al [(Science (1954) 119 , 608-609)] who injected intravenously into rats chelated iron (sodium ethylenediamine tetraacetate ferric - FeEDTA) and observed an extremely poor iron absorption. They concluded that intravenously injected metal ions remained attached to the core of the complex and were not readily available to the body's absorption systems.

The inventors have shown a quick donation of iron from the complexes of the invention to the molecule of Iron absorption from the body, transferrin protein. This is demonstrated by incubation of apotransferrin (i.e. transferrin not bound to iron) with a solution of a complex of the invention. The color of the solution disappears quickly, indicating donation of iron to apotransferrin.

Particularly preferred complexes of the invention comprise the 1: 1 complexes of maltol iron and iron ethyl maltol. It has been discovered that these complexes are approximately ten times more soluble than the ratio complex 1: 3 molar iron / hydroxypyrone.

The advantage of a 1: 1 iron / hydroxypyrone molar ratio complex for pharmaceutical purposes is that it contains an equimolar ratio of iron: hydroxypyrone. For example, ethylmaltol can be administered to the general public at a dose of 2 mg kg -1 body weight 24 h -1 for life. Therefore, for a 50 kg person, a daily dose of 100 mg of ethylmaltol is allowed. In a complex of the invention, 100 mg of ethylmaltol can be associated with 40 mg of iron - a dose suitable for an over-the-counter (OTC) product. Additionally, 1: 1 iron / hydroxypyrone complexes are preferred because they use less hydroxypyrone, leading to cost savings and a reduction in the toxicity concern due to hydroxypyrone per se .

In a third aspect, the invention provides a method to produce a composition for use in medicine that comprises mixing a hydrated ferric salt with a hydroxypyrone to form a 1: 1 molar ratio complex (iron: hydroxypyrone). The resulting solution has a concentration of 10 approximately molar of ferric monohydroxypyrone. Simultaneously or then a carboxylic acid is added to the mixture. Preferably, the method further comprises adding to the mixture a pharmaceutically acceptable carrier, simultaneously or next. Then the mixture can be dried.

Hydrated ferric salt may comprise a counterion as a carboxylic acid, preferably citrate, or ammonium citrate; or a halide, preferably chloride, or nitrate.

Ferric salts are especially preferred. hydrates that include ferric chloride hexahydrate (CAS No. 10025-77-1) and the brown form hydrated ferric ammonium citrate (CAS No. 1332-98-5) or the green form hydrated (CAS No. 1333-002) containing 16.5 - 18.5% and 14.5 - 16% iron and 65% and 75% citric acid respectively.

Preferably, the hydrated ferric salt and the hydroxypyrone and optionally carboxylic acid, are supplied as powders and mixed by crushing.

It will be understood that the above method is especially suitable for producing complexes and compositions of according to the first aspect of the invention. In addition, the invention provides compositions for use in medicine comprising mixtures obtainable by the methods of the second aspect of the invention.

In a further aspect the invention relates to a pharmaceutical composition comprising an iron complex of the invention together with an acceptable diluent or carrier pharmaceutically

In "pharmaceutically acceptable" we include the normal meaning that carriers must be "acceptable" in the sense of being compatible with the active ingredient (complex) and not harmful to receptors thereof.

The composition can be in solid form or liquid Suitable solid carriers include starch, lactose, dextrin and magnesium stearate. Liquid carriers must be sterilized and pyrogen free: solution examples Saline and water.

The complexes of the invention provide special advantages in relation to the formulation of complexes of iron. The liquid formulations of iron complexes are particularly suitable for oral and parenteral administration. In such applications the solubility of some iron complexes Acquaintances is unsatisfactory.

Iron complexes can be formulated with a physiologically acceptable diluent or carrier for use as drugs for veterinary or human use in a variety of ways. However, compositions in which the diluent or carrier is different from a solution not sterilized in water and / or organic solvent. Therefore, iron complexes they can be applied as an aqueous, oily or emulsified composition that incorporates a liquid diluent that, however, will be used more usually for parenteral administration and therefore should be sterilized and pyrogen free. A form of special interest in Both have the form of a sterile injectable solution. Without However, oral administration is generally more preferred for the treatment of iron deficiency anemia in humans and Complexes of the present invention can be given by this route.

Oral administration is often preferred for the treatment of iron deficiency anemia in humans and The compositions of the present invention can be administered by this way. For oral administration in humans it is more usual to use compositions incorporating a solid carrier, for example starch, lactose, dextrin or magnesium stearate. These solid compositions can be conveniently configured by example in the form of tablets, capsules (including Spanish), etc. However, liquid preparations are especially useful. for oral administration to patients who have difficulty swallow solid forms. These difficulties are common in patients suffering from anemias associated with arthritis.

Other forms of administration than by injection or orally, for example the use of suppositories.

In a pharmaceutical composition it can be content more than one iron complex and can also be included Other active compounds. Typical additives include compounds who have the ability to facilitate the treatment of anemia, like folic acid. You can also include a source of zinc.

The iron compounds used in the Iron deficiency anemia treatment can inhibit the zinc absorption mechanism in the body. This can produce serious side effects on the fetus when pregnant women They are anemia.

The iron complexes of the present invention they are advantageous because they do not show this effect in any way or show lower levels of known compounds for the Anemia treatment Consequently they are required only Small amounts of zinc source if some.

The compositions are particularly useful for mild anemias where a lower daily dose of iron allows a Better treatment compliance. Other approaches may include various types of controlled release systems, which provide a delayed release of complex over time, or a system that be resistant to dissociation under acidic conditions for example, by using a buffer or a system that tilts to the release in the conditions found in the intestine thin. These may be a pH sensitive system that is stabilized towards a typical 1 to 3 pH of the stomach but at one of 7 to 9 typical of the small intestine. As the pH of the stomach is more elevated after a meal, it can be advantageous, whatever the method or formulation used, administer iron complexes in this moment.

The present invention includes a method for treatment of a patient that increases iron levels in the blood flow of the patient comprising administering to said patient an effective amount of an iron complex like the defined above.

In addition to pharmaceutical uses, complexes of iron also have utility as a source of iron in other various applications that include cell growth media animal, bacterial and vegetable, or in coloring agents and also in Iron transport control through membranes.

The iron complexes of the invention can be prepare by reaction of hydroxypyrone and iron ions, being conveniently derived the latter from an iron salt, particularly of a ferric halide and especially chloride iron. The reaction is conveniently carried out in a solvent. adequate mutual and for this purpose water can be used frequently. However, if desired a solvent mixture can be used aqueous / organic or an organic solvent, for example, ethanol, methanol, acetone and chloroform and mixtures of these solvents together and / or with water if appropriate. In particular, methanol can be used or especially ethanol when it is desired to carry out the separation of al minus a major part of byproduct, such as sodium chloride, by precipitation while the iron complex is retained in solution.

The compositions can be formulated in the form of unit dose, that is in the form of discrete portions containing a unit dose, or a multiple or subunit dose. Although the given dosage of hydroxypyrone iron complex will depend on several factors including the particular compound that be used in the composition, it can be stated as a guide that the maintenance of a satisfactory level of the amount of iron present in the human body will be achieved using a dosage daily, in terms of the iron content of the compound, which falls in a range from about 0.1 to 100 mg and frequently in the range from 0.5 to 10 mg, for example 1 or 2 mg, the doses being veterinarians of a similar ratio g / kg body weight. Do not However, it will be understood that it may be suitable in certain circumstances administer daily doses above or below these levels. In general, the goal would be to provide the amount of iron required by the patient without administering a undue excess and the properties of pharmaceutical compositions in accordance with the present invention is particularly adjusted to achieve this goal. Similarly, the concentration of iron in the pharmaceutical composition in the form of a complex of hydroxypyrone can vary quite widely, for example in a range from 0.01 to 20% weight / weight. However it is more usual that the concentration exceeds 0.01% w / w and can often exceed 0.05 or 0.1%, while a more usual limit for upper end of the range is 13% w / w. An interval concentration current is 0.05 to 5% w / w, for example, 0.2 a 0.5, 1 or 2% p / p.

The present invention further includes the use of a iron complex of the invention comprising 3-hydroxy-4-pyrone or from 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms linked to atoms of carbon are replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, for the manufacture of a medicament for use in effecting an increase in the iron levels of the flow blood of a patient.

In a further aspect, the invention provides a composition comprising a complex of the invention mixed with a complexed hydroxypyrone complex.

A small excess of complex non-formed hydroxypyrone is advantageous because any free iron can be chelated (formed with) in vivo , making the iron available for bioabsorption.

The molar ratio of the non-formed hydroxypyrone complex (free) with the iron complex must be selected so that the amount of chelated iron (complex formed) available for absorption is maximized in vivo and substantially complex with molar ratio 1 is not generated: 3. A preferred range of free hydroxypyrone molar ratio present in the compositions according to the present invention is therefore up to 1 mole of free hydroxypyrone: 1 mole of hydroxypyrone iron complex. Conveniently, a ratio of up to no more than 0.25 moles: 1 mole with a lower level of less than 0.25 moles: 1 mole, with less than 0.15 moles: 1 mole being especially preferred.

Embodiments of the invention by way of example with reference to the following figures and examples:

Fig. 1 shows the absorption profile of iron from an iron complex: molar ratio hydroxypyrone 1: 1 and citrate according to a first aspect of the invention; Y

Example 1 Human test in vivo Method

A man who had fasted for 24 hours orally administered a composition of the invention comprising Ferric monomaltol citrate with 300 mg as iron in 5 ml of water. The concentration of iron in plasma in the blood flow of subject was determined by the ICP technique [plasma coupled inductively, (Machine Jobin Yvonne Model 20)] which determines the emission spectrum of the elements by optical spectrometry when the samples are subjected to a very hot flame. The technique It is very sensitive and the accuracy and precision is less than + or - 1%.

The results are presented in Table 1 and in the Fig. 1.

TABLE 1

3

The idle value (zero time) of 1.2 µg / ml (21.8 µmol / liter) agrees with the normal range of 13-32 \ mumol / liter found by others techniques and the rise is comparable to that found in normal for standard iron preparations.

Example 2 Dry mixing method

1) 276 mg of ferric trimaltol, a Intense burgundy red powder, with 325 mg of ferric citrate (CAS No. 3522-50-7), a reddish brown powder paler and 126 mg of anhydrous citric acid (CAS No. 79-92-9). Dust red-brown produced was an intermediate color between ferric trimaltol and ferric citrate. The iron relationship: maltol: citrate was in the previous mixture 1: 1: 1. Powder color resulting remained stable when kept dry room temperature. Although individual ferric chelates they have limited solubility (towards 10 mg / ml) and need heat for its dissolution, the mixture had remarkable properties after addition of water in the rapid formation of citrate complexes of highly soluble ferric monomaltol with a distinctive red hue purple or orange red depending on the pH and concentration. The spectral analysis of solutions in an interval UV-vis using a Hewlett spectrophotometer Packard SP200, confirmed the formation of compositions of monomaltol

2) 430 mg of ferric trimaltol was crushed with 534 mg of ferric ammonium citrate (CAS No. 1185-57-5) and 192 mg of citric acid anhydrous (CAS No. 77-92-9) being the resulting mixture a reddish brown powder. The resulting solutions they had a distinctive red-orange color and the spectral analysis showed them as stable for many months at different pH values.

3) 250 mg of ferric citrate (CAS No. 3522-50-7), or 270 mg citrate ferric ammonium (CAS No. 1185-57-5) with 130 mg of maltol (CAS No. 118-71-8). The resulting mixtures they gave a pale brown powder and pale yellow mustium respectively, that when they were kept at room temperature in dry state for long periods (> 6 months) remained unchanged When the powders were added to water, ClH 1-4 normal and water containing stabilizer sodium bicarbonate at pH 6.4 solutions, after a yellow color transient, they turned from purple to orange reds depending on the pH with spectra identical to those of the solutions generated in 1) and 2).

The inventors have demonstrated by analysis infrared spectroscopic than the components of the mixtures previous solids are stable, that is, there is no reaction appreciable among the components.

Example 3 Preparation of iron salt citrate (III) monoethyl maltol

To form an iron complex: hydroxypyrone 1: 1 with citrate according to the first aspect of the invention, dissolved iron (III) citrate in non-stabilized water with a concentration between 0.1 and 1 M. An equivalent amount of Ethylmaltol (dissolved in ethanol) to the solution with rapid stirring. An intense red solution of citrate -2 [Fe III]. ethylmaltol] + 2. After stir for 15 min. the ethanol was removed by evaporation at atmospheric pressure. The resulting solution was dried by freezing to produce an intense red powder.

Example 4 Solubility of iron / hydroxypyrone complexes with citrate

The inventors examined whether a ternary complex of citric acid (1), ethyl maltol (2) and iron (III) is stable in aqueous systems in the pH range 3.0-7.0. In principle a citric acid molecule (binder tetradenticulate) and a molecule of ethylmaltol (binder bidenticulate) can provide an octahedral field for the iron (III) (3).

4

5

where R is ethyl.

Several solutions of iron (III) and ethylmaltol are stabilized at pH 7.0 with propane morpholine sulphonate (MOPS) 50 mM; at pH 5.0 with sodium acetate (50 mM) and at pH 3.0 with glycine (50 mM). Iron (III) 9H 2 O nitrate was used as a source of iron (III) but other solutions such as citrate could be used of iron.

The solutions were visually investigated by the precipitate formation and underwent spectroscopy UV-V The resulting spectra were compared with published calculated spectra of [iron (III) .maltol] 2+, [iron (III) .maltol2] + and [iron (III). (maltol) 3] º.

(a) [Fe III] at 0.1 M

The preparation Iron / Citric acid / Ethylmaltol led to the formation of a precipitate. The inspection of purple brown precipitate by spectroscopy led to his Identification as the neutral iron / ethylmaltol 1: 3 complex. He Supernatant spectrum was characterized by a mixture of Iron / Ethylmaltol complex 1: 2 and 1: 3 with citrate as an anion. Surprisingly, there was no evidence of the Iron Ternary Complex / Ethylmaltol / Citric acid 1: 1: 1 in the range 3.0 - 7.0.

To form a liquid preparation of the invention the precipitate iron / ethylmaltol 1: 3 is removed by example, by filtration. The precipitate can be used to Formulate a solid composition of the invention.

(b) [Fe III] at 0.01 M and at 0.001 M

The mixture Iron / Ethylmaltol / Citric acid is discovered that it was soluble at pH 3.0 at 0.01 iron concentration M. However, after remaining at rest for approximately 12 h, an intense red precipitate developed. This precipitate is characterized as a complex Iron / Ethylmaltol 1: 3. Lower acidity (pH 5.0 and 7.0) a similar precipitate formed immediately. The Spectroscopy demonstrated the existence of both iron complexes / Ethylmaltol 1: 2 and 1: 3 in the supernatant at all pH values investigated

To form a liquid preparation of the invention the precipitate iron / ethylmaltol 1: 3 is removed, by example by filtration. The precipitate can be used in the formulation of a solid composition of the invention.

At iron concentrations of 0.001 M (5.6 mg of iron / 100 ml) no precipitate was observed in the presence simultaneous citric acid and ethylmaltol at any of the values of pH investigated. In addition there was no evidence of the formation of ternary complex, the observed spectra of these being similar solutions to those observed in the absence of citrate. However, at this lower concentration no precipitate forms and a stable liquid preparation of the invention.

Effect of carboxylic acid, citrate

The inventors have discovered that, in the absence of citric acid, the dominant iron species are indicated by equations 1, 2 and 3. The last two equations represent disproportions of iron complexes, (L represents a hydroxypyrone binder).

7

In a system with equimolar amounts of iron and ethylmaltol iron complex is highly favored (FeL 2+). As the pH of the solution increases, the 1: 2 and 1: 3 complexes, but only in the presence of excess binder. In a situation with an eqimolar relationship, you are species can only form by disproportion of complexes 1: 1 and 1: 2 (ecs 2 and 3). This leads to the formation of insoluble hydrated Fe 3+ cation.

The situation is different in the presence of acid citric. In principle, the ternary complex (3) can be formed (ec 4) but also a disproportion of the Iron / Ethylmaltol complex 1: 1 is simpler since this disproportion produces the complex iron (III) citrate (ec 5) and not simply iron (III) hydrous.

\hskip1cm

FeL^{2+} + Cit^{3-}

\hskip0.5cm

FeL. Cit^{-}

\hskip7.4cm

ec 4

 \ hskip1cm 

FeL 2+ + Cit 3-

 \ hskip0.5cm 

FeL. Cit -

 \ hskip7.4cm 

ec 4

\hskip1cm

2FeL^{2+} + Cit^{3-}

\hskip0.5cm

FeL_{2} + FeCit^{0}

\hskip6.6cm

ec 5

 \ hskip1cm 

2FeL 2+ + Cit 3-

 \ hskip0.5cm 

FeL 2 + FeCit 0

 \ hskip6.6cm 

ec 5

The spectral evidence observed shows that the reaction outlined by ec 5 dominates the aqueous chemistry of this system in the pH range 3-7.

No evidence could be found of the existence of complex (3) Iron (III) / Ethylmaltol / Citric acid. Therefore, in solution or in vivo the citrate behaves as a counterion (anion) of the iron / hydroxypyrone complex and improves the solubility of the 1: 2 and 1: 1 complexes, which constitute the intermediate products of iron / hydroxypyrone dissociation 1 : 3, instead of forming the predicted mixed binder complexes. Any excess iron generated is trapped as iron citrate instead of being precipitated as forms of insoluble hydrated iron. The solubility improvement achieved by citrate keeps iron available for absorption in vivo . This means that the solid and liquid pharmaceutical preparations of the invention do not need to contain as much iron or hydroxypyrone as conventional preparations.

Claims (30)

1. An iron complex comprising iron in the ferric state and a hydroxypyrone binder and characterized in that iron and hydroxypyrone are supplied in combination with a carboxylic acid as counterion. 2. An iron complex as claimed in claim 1 wherein the carboxylic acid is an acid hydroxycarboxylic. 3. An iron complex as claimed in claim 1 or 2 wherein the carboxylic acid comprises from 1 to 6 carbon atoms 4. An iron complex as claimed in any one of claims 1 to 3 wherein the carboxylic acid It has 1 to 3 carboxylic groups. 5. An iron complex as claimed in any one of claims 1 to 4, wherein the acid is select from one or more citric acid, isocitric acid, gluconic acid, succinic acid, fumaric acid and acid Tartaric 6. An iron complex as claimed in any one of claims 1 to 4, wherein the carboxylic acid It is citric acid. 7. An iron complex as claimed in any one of claims 1 to 6, wherein the hydroxypyrone is 3-hydroxy-4-pyrone. 8. An iron complex as claimed in claim 7, wherein the 3-hydroxy-4-pyrone It is maltol or ethylmaltol. 9. An iron complex as claimed in claim 8, wherein the maltol or ethylmaltol is in a binder complex mixed with iron. 10. An iron complex as claimed in any of claims 7 to 9, wherein the iron ion is in combination with the 3-hydroxy-4-pyrone as a 1: 3, 1: 2 and / or 1: 1 molar ratio complex (iron / hydroxypyrone). 11. An iron complex as claimed in claim 10, wherein the complex comprises a complex of 1: 1 molar ratio of ferric maltol or ferric ethylmaltol. 12. A method to prepare a complex such as claimed in any preceding claim comprising react ferric iron and hydroxypyrone in solution and add carboxylic acid where the components are present in equivalent molar ratios to form a 1: 1: 1 complex of iron: hydroxypyrone: carboxylic acid. 13. A method to prepare a complex such as claimed in any one of claims 1 to 10 that comprises providing a solution of iron (III) citrate and Mix it with a hydroxypyrone solution. 14. A pharmaceutical composition comprising an effective amount of at least one complex as claimed in any one of claims 1 to 11 and a carrier pharmaceutically acceptable. 15. A pharmaceutical composition such as claimed in claim 14 wherein the citric acid is present in an amount from 10 to 1000 mg per dose. 16. A method of producing a composition of iron for use in medicine comprising mixing a compound of ferric iron, different from an inorganic ferric salt; and one hydroxypyrone where the iron compound and hydroxypyrone are they mix in a dry state and the mixture also includes an acid carboxylic, where the iron composition is capable of forming a iron complex according to any of the claims 1 to 11 17. A method as claimed in the claim 16 wherein the iron compound comprises a ferric carboxylate. 18. A method as claimed in the claim 17 wherein the ferric carboxylate is ferric citrate and / or ferric ammonium citrate. 19. A method as claimed in any of claims 16 to 18, wherein hydroxypyrone is provided in form of ferric hydroxypyrone complex with a molar ratio iron: hydroxypyrone 1: 3. 20. A method as claimed in any of claims 16 to 19, wherein the components of the mixture They are supplied in powder form. 21. A method to produce a complex of according to any of claims 1 to 11 for use in medicine comprising mixing a hydrated ferric salt with a hydroxypyrone to form a 1: 1 molar ratio complex (iron : hydroxypyrone) and add simultaneously or subsequently to the mixture carboxylic acid. 22. A method as claimed in the claim 21, wherein the hydrated ferric salt is a carboxylate selected from a citrate and / or ammonium citrate and / or a halide selected from chloride and / or nitrate. 23. A composition for use in medicine obtainable by the method claimed in any of the claims 16 to 22. 24. A pharmaceutical composition such as claimed in any of claims 14 and 15, wherein the Pharmaceutically acceptable carrier is a solid. 25. A pharmaceutical composition such as claimed in any of claims 14 and 15, wherein the Pharmaceutically acceptable diluent is a liquid. 26. A pharmaceutical composition such as claimed in any of claims 14 and 15 adapted For oral administration. 27. A pharmaceutical composition such as claimed in claim 24 in tablet form. 28. A pharmaceutical composition such as claimed in claim 24 in the form of a suppository. 29. A pharmaceutical composition such as claimed in claim 25 adapted for injection intravenous or intramuscular. 30. Use of a complex as claimed in any of claims 1 to 11 in the manufacture of a medication for use in increasing the level of iron in the blood flow of a patient